17-8888854-T-C

Position:

• chr17-8888854-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142633.3(PIK3R5):​c.933A>G​(p.Leu311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,604,864 control chromosomes in the GnomAD database, including 68,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6344 hom., cov: 33)
  • Exomes 𝑓: 0.29 (62231 hom.)
• Consequence: PIK3R5 NM_001142633.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.786

Genes affected

PIK3R5 (HGNC:30035): (phosphoinositide-3-kinase regulatory subunit 5) Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found. [provided by RefSeq, Oct 2011]

LOC124903922 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-8888854-T-C is Benign according to our data. Variant chr17-8888854-T-C is described in ClinVar as [Benign]. Clinvar id is 129895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8888854-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.786 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R5	NM_001142633.3	c.933A>G	p.Leu311=	synonymous_variant	10/19	ENST00000447110.6	NP_001136105.1
LOC124903922	XR_007065613.1	n.79+1154T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R5	ENST00000447110.6	c.933A>G	p.Leu311=	synonymous_variant	10/19	5	NM_001142633.3	ENSP00000392812	P4

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42375 AN: 151962 Hom.: 6327 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.299

GnomAD3 exomes AF: 0.248 AC: 59355 AN: 239436 Hom.: 8501 AF XY: 0.245 AC XY: 31919 AN XY: 130230

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.000713

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.285 AC: 414544 AN: 1452784 Hom.: 62231 Cov.: 38 AF XY: 0.281 AC XY: 202809 AN XY: 722874

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.320

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.279 AC: 42427 AN: 152080 Hom.: 6344 Cov.: 33 AF XY: 0.269 AC XY: 19969 AN XY: 74362

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.296

Alfa AF: 0.291 Hom.: 1383

Bravo AF: 0.289

Asia WGS AF: 0.0920 AC: 321 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.310

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ataxia with oculomotor apraxia type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11650737; hg19: chr17-8792171; COSMIC: COSV52653686; COSMIC: COSV52653686;